The overall goal of this application is to support the Principal Investigator's efforts in developing a career performing high-caliber patient-oriented research focusing on the metabolic toxicities of antiretroviral therapy. To accomplish this goal, a mentored program of didactic and scientific training is. proposed which includes didactic training through the Clinical Research Scholars Program (CRSP) at Case Western Reserve University (CWRU) and coursework that is part of the Center for Medical Education and Research Development (CMERAD) Program at the Cleveland Clinic Lerner College of Medicine (CCLCM) of CWRU, mentoring and scientific advisory committee consisting of experts in the areas of HIV and metabolic and cardiovascular diseases has been assembled to assist the principal investigator in her efforts to establish a career in patient-oriented research. She will have the full support of the Cleveland Clinic's outstanding research environment. The primary goal of this application is to decrease the morbidity associated with HIV and antiretroviral therapy (ART)-associated metabolic toxicities by evaluating strategies to improve lipoatrophy and subclinical atherosclerosis. To meet these goals, this application has the following specific aims: 1) Evaluate the efficacy of pioglitazone on limb fat and fat mitochondrial DNA in HIV-infected subjects with lipoatrophy treated with thymidine-sparing regimens 2) Evaluate the efficacy of pioglitazone on the metabolic syndrome and underlying atherosclerosis. The hypotheses will be tested using a 48-week prospective, randomized, placebo-controlled trial. Long-term consequences of potent antiretroviral therapy including the metabolic complications of lipodystropohy, insulin resistance and atherosclerotic disease have emerged as a major potential limitation to this life-saving treatment. HIV-related metabolic complications to ART are also likely to have a future increasing global impact as more HIV-infected persons in developing countries gain access to ART.